Parmeet K. Manchanda

The Ohio State University

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Rama Devi Mittal

Sanjay Gandhi Post Graduate Institute of Medical Sciences

Hemant K. Bid

Morehouse College

Eric J. Ley

Cedars-Sinai Medical Center

Jeffrey S. Scehnet

University of Southern California

Valery Krasnoperov

VasGene Therapeutics (United States)

Fred A. Weaver

University of Southern California

J. B. Singh

Panjab University

Robert D. Ladner

Queen's University Belfast

Robert W. Beart

Creighton University

Debra Hawes

University of Southern California

Cooperative Institutions

The Ohio State University

Sanjay Gandhi Post Graduate Institute of Medical Sciences

University of Southern California

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Ohio State University Wexner Medical Center

Southern California University for Professional Studies

City of Hope

Cancer Genetics (United States)

National Cancer Institute

Society of General Internal Medicine

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Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression

Cancer Research (2009)

Sunil Kumar Jeffrey S. Scehnet Eric J. Ley J. B. Singh Valery Krasnoperov

Abstract The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein–binding protein (CBP) over p300 by the Wnt/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand–mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736–45]

Tumor progression

Tumor M2-PK

10.1158/0008-5472.can-08-3232

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Citations (124)

Follicular Thyroid Cancers Demonstrate Dual Activation of PKA and mTOR as Modeled by Thyroid-Specific Deletion of Prkar1a and Pten in Mice

The Journal of Clinical Endocrinology & Metabolism (2014)

Daphne R. Pringle Vasily Vasko Lianbo Yu Parmeet K. Manchanda Audrey A. Lee

Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC.The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC.We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals.Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases.There were no interventions.Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression.Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement.These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.

Follicular thyroid cancer

10.1210/jc.2013-3101

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Citations (33)

Ethnicity greatly influences the interleukin-1 gene cluster(IL-1b promoter, exon-5 and IL-1Ra) polymorphisms: a pilot study of a north Indian population.

PubMed (2006)

Parmeet K. Manchanda Hemant K. Bid Rama Devi Mittal

There is considerable evidence that polymorphisms in the regulatory regions of cytokine genes are highly influenced by ethnicity. Polymorphisms in interleukin 1-beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) genes, respectively encoding a potent inflammatory agent and an antagonist, which combines with IL-1 receptors competitively, have been associated with a number of diseases like systemic lupus erythematosus, rheumatoid arthritis, sepsis, kidney diseases, and cancer. In this study, we therefore evaluated the distribution of interleukin-1 gene cluster (IL-1beta promoter region, exon-5 and IL-1Ra) gene polymorphisms in 206 healthy north Indian subjects, using PCR-based restriction analysis. We also constructed various haplotypes and estimated the linkage disequilibrium (LD). We found that genotype and allelic frequencies for these cytokines were conspicuously different when compared among different ethnic populations. The haplotype 'T-E1-1' predominated (41.7%) while the least common was 'C-E2-2' (2%) in our population. Genetic linkage between three loci of IL-1 gene showed strong association among the variants in controls (D'=0.42, p<0.001). Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from other populations and ethnic groups. Thus they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.

Linkage Disequilibrium

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Analysis of polymorphisms of tumor necrosis factor‐α and polymorphic xenobiotic metabolizing enzymes in inflammatory bowel disease: Study from northern India

Journal of Gastroenterology and Hepatology (2006)

Rama Devi Mittal Parmeet K. Manchanda Hemant K. Bid Uday C. Ghoshal

Abstract Background: Tumor necrosis factor (TNF)‐α is a proinflammatory cytokine associated with inflammatory diseases, while GSTM1 and T1 enzymes catalyze detoxification of products of oxidative stress and hence reduce inflammation. Thus, both may play important roles in the pathogenesis of inflammatory bowel disease (IBD). The present study aimed to evaluate the effect of polymorphism of the TNF‐α promoter at the −308 site, GSTM1 and GSTT1 in patients with IBD and healthy controls from northern India. Method: Genotyping was performed in 114 patients with IBD (22 Crohn’s disease [CD] and 92 ulcerative colitis [UC]) in TNF‐α and 105 (20 CD and 85 UC) in GSTM1 and T1 and 164 healthy controls using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and multiplex PCR methods. Results: Patients with IBD were comparable to healthy controls in relation to age and gender. Genotypic and allelic frequencies of TNF‐α were comparable among patients with IBD and healthy controls. GSTM1 null genotype was more frequent in UC than in healthy controls (52/85 vs 49/164; P < 0.001) and GSTT1 null genotype was more frequent both in UC and CD as compared to healthy controls (77/85 and 18/20 vs 26/164, respectively; P < 0.001 for both). Frequency of combined null genotype in GSTM1 and T1 was more frequently associated with IBD than healthy controls (4/20 vs 8/164; P = 0.029, OR = 4.875 and 28/85 vs 8/164; P < 0.001, OR = 9.579, respectively). Conclusions: ‘Null’ genotypes of GSTM1 and T1 are associated with IBD and the combination of the two GST genotypes further increases the risk, possibly due to gene–gene interaction. TNF‐α is unlikely to be an important determinant of susceptibility to IBD in the Indian population.

Proinflammatory cytokine

Pathogenesis

10.1111/j.1440-1746.2006.04538.x

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Citations (43)

Analysis of cytokine gene polymorphisms in recipient’s matched with living donors on acute rejection after renal transplantation

Molecular and Cellular Biochemistry (2007)

Parmeet K. Manchanda Rama Devi Mittal

10.1007/s11010-007-9694-0

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Citations (43)

Association of interleukin (IL)-4 intron-3 and IL-6 −174 G/C gene polymorphism with susceptibility to end-stage renal disease

Immunogenetics (2007)

Rama Devi Mittal Parmeet K. Manchanda

10.1007/s00251-006-0182-6

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Citations (60)

Supplementary Figures 1-11 from Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression

S. Ram Kumar Jeffrey S. Scehnet Eric J. Ley J. B. Singh Valery Krasnoperov

Supplementary Figures 1-11 from Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression

10.1158/0008-5472.22381299.v1

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Data from Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression

S. Ram Kumar Jeffrey S. Scehnet Eric J. Ley J. B. Singh Valery Krasnoperov

<div>Abstract<p>The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein–binding protein (CBP) over p300 by the Wnt/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand–mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736–45]</p></div>

Tumor progression

Tumor M2-PK

10.1158/0008-5472.c.6499827.v1

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Predisposition of genetic polymorphism with the risk of urolithiasis

Indian Journal of Clinical Biochemistry (2008)

Rama Devi Mittal Hemant K. Bid Parmeet K. Manchanda Rakesh Kapoor

Candidate gene

Linkage Disequilibrium

Genetic Association

10.1007/s12291-008-0027-1